US6127372A - Sulfonamide inhibitors of aspartyl protease - Google Patents
Sulfonamide inhibitors of aspartyl protease Download PDFInfo
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- US6127372A US6127372A US08/424,372 US42437296A US6127372A US 6127372 A US6127372 A US 6127372A US 42437296 A US42437296 A US 42437296A US 6127372 A US6127372 A US 6127372A
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- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
- C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/41—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
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- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
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- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D233/72—Two oxygen atoms, e.g. hydantoin
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Abstract
Description
______________________________________ Designation Reagent or Fragment ______________________________________ Ac acetyl Me methyl Et ethyl Bn benzyl Trityl triphenylmethyl Asn D- or L-asparagine Ile D- or L-isoleucine Phe D- or L-phenylalanine Val D- or L-valine Boc tert-butoxycarbonyl Cbz benzyloxycarbonyl (carbobenzyloxy) Fmoc 9-fluorenylmethoxycarbonyl DCC dicyclohexylcarbodiimide DIC diisopropylcarbodiimide EDC 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride HOBt 1-hydroxybenzotriazole HOSu 1-hydroxysuccinimide TFA trifluoroacetic acid DIEA diisopropylethylamine DBU 1,8-diazabicyclo(5.4.0)undec-7-ene EtOAc ethyl acetate t-Bu tert-butyl iBu iso-butyl DMF dimethylformamide THP tertrahydropyran THF tetrahydrofuran DMSO dimethylsulfoxide ______________________________________
TABLE 1 __________________________________________________________________________ ##STR14## COMPOUND OH Z G D' R.sup.7 __________________________________________________________________________ XVI R,S ##STR15## H.sub.2 i-Bu 4-OCH.sub.3 XVII R,S ##STR16## H.sub.2 i-Bu 4-OCH.sub.3 XVIII R,S ##STR17## O i-Bu 4-OCH.sub.3 XIX R,S ##STR18## H.sub.2 i-Bu 4-OCH.sub.3 XX R,S ##STR19## H.sub.2 i-Bu 4-OCH.sub.3 XXI R,S ##STR20## H.sub.2 ##STR21## 4-OCH.sub.3 LXV R,S ##STR22## H.sub.2 ##STR23## 4-OCH.sub.3 XXII R,S ##STR24## H.sub.2 ##STR25## 4-OCH.sub.3 1000 R ##STR26## H.sub.2 ##STR27## 4-OCH.sub.3 1001 S ##STR28## H.sub.2 ##STR29## 4-OCH.sub.3 XXIV R,S ##STR30## H.sub.2 ##STR31## 4-OCH.sub.3 1002 R,S ##STR32## H.sub.2 i-Bu 4-OCH.sub.3 1003 S ##STR33## H.sub.2 ##STR34## 4-OCH.sub.3 1004 S ##STR35## H.sub.2 ##STR36## 4-OCH.sub.3 1005 S ##STR37## H.sub.2 ##STR38## 4-OCH.sub.3 1006 S ##STR39## H.sub.2 ##STR40## 4-OCH.sub.3 1007 S ##STR41## H.sub.2 ##STR42## 4-OH 1008 S ##STR43## H.sub.2 ##STR44## 4-NH.sub.2 1009 S ##STR45## H.sub.2 ##STR46## 3-NH.sub.2 1010 S ##STR47## H.sub.2 ##STR48## 4-OCH.sub.3 1011 S ##STR49## H.sub.2 ##STR50## 4-OCH.sub.2 1012 S ##STR51## H.sub.2 i-Bu 3-NH.sub.2 1013 S ##STR52## H.sub.2 ##STR53## 3-NH.sub.2 1014 S ##STR54## H.sub.2 ##STR55## 3-NH.sub.2 1015 S ##STR56## H.sub.2 ##STR57## 4-OCH.sub.3 1016 S ##STR58## H.sub.2 ##STR59## 4-OCH.sub.3 1017 S ##STR60## H.sub.2 ##STR61## 4-OCH.sub.3 1018 S ##STR62## H.sub.2 ##STR63## 4-OCH.sub.3 1019 S ##STR64## H.sub.2 ##STR65## 4-OCH.sub.3 1020 S ##STR66## H.sub.2 ##STR67## 4-OCH.sub.3 1021 S ##STR68## H.sub.2 ##STR69## 4-OCH.sub.3 1022 S ##STR70## H.sub.2 ##STR71## 4-OCH.sub.3 1023 S ##STR72## H.sub.2 ##STR73## H 1024 S ##STR74## H.sub.2 ##STR75## 4-OCH.sub.3 1025 S ##STR76## H.sub.2 ##STR77## 4-OCH.sub.3 1026 S ##STR78## H.sub.2 ##STR79## 4-OCH.sub.3 1027 R,S ##STR80## H.sub.2 ##STR81## 4-OCH.sub.3 1028 S ##STR82## H.sub.2 ##STR83## 4-OCH.sub.3 1029 S ##STR84## H.sub.2 ##STR85## 4-OCH.sub.3 1043 S ##STR86## H.sub.2 ##STR87## 3-NH.sub.2 1044 S ##STR88## H.sub.2 ##STR89## 3-NH.sub.2 1045 S ##STR90## H.sub.2 ##STR91## 3-NH.sub.2 1046 R,S ##STR92## H.sub.2 ##STR93## 4-OCH.sub.3 1047 S ##STR94## H.sub.2 ##STR95## 4-OCH.sub.3 1048 R,S ##STR96## H.sub.2 ##STR97## 4-OCH.sub.3 1125 R,S ##STR98## H.sub.2 ##STR99## 3-NH.sub.2 __________________________________________________________________________
TABLE 2 __________________________________________________________________________ ##STR100## COMPOUND Z D' E' __________________________________________________________________________ 1050 ##STR101## ##STR102## ##STR103## 1051 ##STR104## ##STR105## t-Bu 1052 ##STR106## ##STR107## ##STR108## 1053 ##STR109## ##STR110## ##STR111## 1054 ##STR112## ##STR113## ##STR114## 1055 ##STR115## ##STR116## ##STR117## 1056 ##STR118## ##STR119## ##STR120## 1057 ##STR121## ##STR122## ##STR123## 1058 ##STR124## ##STR125## ##STR126## 1059 ##STR127## ##STR128## ##STR129## 1060 ##STR130## ##STR131## ##STR132## 1061 ##STR133## ##STR134## ##STR135## 1062 ##STR136## ##STR137## ##STR138## 1063 ##STR139## ##STR140## ##STR141## 1064 ##STR142## ##STR143## ##STR144## 1065 ##STR145## ##STR146## ##STR147## 1066 ##STR148## ##STR149## ##STR150## 1067 ##STR151## ##STR152## ##STR153## 1068 ##STR154## ##STR155## ##STR156## 1069 ##STR157## ##STR158## ##STR159## 1070 ##STR160## ##STR161## ##STR162## 1071 ##STR163## ##STR164## ##STR165## 1072 ##STR166## ##STR167## ##STR168## 1073 ##STR169## ##STR170## ##STR171## 1074 ##STR172## ##STR173## ##STR174## 1075 ##STR175## ##STR176## ##STR177## 1076 ##STR178## ##STR179## ##STR180## 1077 ##STR181## ##STR182## ##STR183## 1078 ##STR184## ##STR185## ##STR186## 1079 ##STR187## ##STR188## ##STR189## 1080 ##STR190## ##STR191## ##STR192## 1081 ##STR193## ##STR194## ##STR195## 1082 ##STR196## ##STR197## ##STR198## 1083 ##STR199## ##STR200## ##STR201## 1084 ##STR202## ##STR203## ##STR204## 1085 ##STR205## ##STR206## ##STR207## __________________________________________________________________________
TABLE 3 __________________________________________________________________________ ##STR208## COMPOUND Z X Y R.sup.7 __________________________________________________________________________ XXXIV ##STR209## ##STR210## H 4-NH.sub.2 LXVIII ##STR211## ##STR212## H 4-OCH.sub.3 XXXV ##STR213## H ##STR214## 4-NH.sub.2 LXIX ##STR215## H ##STR216## 4-OCH.sub.3 La ##STR217## H i-Bu 4-OCH.sub.3 Lb ##STR218## H ##STR219## 4-OCH.sub.3 Lc ##STR220## i-Bu H 4-OCH.sub.3 Ld ##STR221## H ##STR222## 4-OCH.sub.3 Lf ##STR223## H ##STR224## 4-OCH.sub.3 __________________________________________________________________________
TABLE 4 __________________________________________________________________________ ##STR225## COMPOUND Z D D' R.sup.7 __________________________________________________________________________ XL ##STR226## ##STR227## ##STR228## 4-OCH.sub.3 LXX ##STR229## ##STR230## ##STR231## 4-OCH.sub.3 LXXI ##STR232## ##STR233## ##STR234## 4-OCH.sub.3 LIV ##STR235## ##STR236## i-Bu 4-OCH.sub.3 LXXII ##STR237## ##STR238## i-Bu 4-OCH.sub.3 LXXIII ##STR239## ##STR240## i-Bu 4-OCH.sub.3 __________________________________________________________________________
TABLE 5 __________________________________________________________________________ ##STR241## COMPOUND Z G X X' D' R.sup.7 __________________________________________________________________________ XLI ##STR242## H.sub.2 OH H i-Bu 4-OCH.sub.3 1030 ##STR243## O OH H i-Bu 4-OCH.sub.3 LXXXV ##STR244## H.sub.2 OH (R,S) H (R,S) i-Bu 4-OCH.sub.3 XLIII ##STR245## H.sub.2 OH H i-Bu 4-OCH.sub.3 XLVI ##STR246## H.sub.2 OH (R,S) H (R,S) i-Bu 4-OCH.sub.3 XLVII ##STR247## H.sub.2 OH (R,S) H (R,S) i-Bu 4-OCH.sub.3 LXXXIII ##STR248## O OH (R,S) H (R,S) i-Bu 4-OCH.sub.3 1031 ##STR249## O OH H i-Bu 4-OCH.sub.3 1032 ##STR250## O OH H i-Bu 4-OCH.sub.3 1033 ##STR251## H.sub.2 OH H i-Bu 4-OCH.sub.3 1036 ##STR252## H.sub.2 OH H i-Bu 4-OCH.sub.3 1037 ##STR253## H.sub.2 OH H i-Bu 4-OCH.sub.3 1038 ##STR254## H.sub.2 OH H i-Bu 4-OCH.sub.3 1039 ##STR255## H.sub.2 OH H i-Bu 4-OCH.sub.3 1040 ##STR256## H.sub.2 OH H i-Bu 4-OCH.sub.3 1042 ##STR257## H.sub.2 OH H i-Bu 4-OCH.sub.3 __________________________________________________________________________
TABLE 6 __________________________________________________________________________ ##STR258## COMPOUND OH R.sup.7 D' D E __________________________________________________________________________ XLIVa S 4-OCH.sub.3 i-Bu i-Bu ##STR259## XLIVb R 4-OCH.sub.3 i-Bu i-Bu ##STR260## XLV S 4-OH i-Bu ##STR261## ##STR262## XLIX S 4-NH.sub.2 ##STR263## ##STR264## ##STR265## LVa S 4-OCH.sub.3 i-Bu ##STR266## ##STR267## LVb R 4-OCH.sub.3 i-Bu ##STR268## ##STR269## 1034 S 4-OCH.sub.3 i-Bu i-Bu --N(CH.sub.3).sub.2 1035 S 4-OCH.sub.3 i-Bu ##STR270## ##STR271## 1041 S 4-OCH.sub.3 i-Bu ##STR272## ##STR273## 1086 S 4-OCH.sub.3 i-Bu ##STR274## ##STR275## 1087 S 4-OCH.sub.3 i-Bu ##STR276## t-Bu 1088 S 4-OCH.sub.3 i-Bu ##STR277## ##STR278## 1089 S 4-OCH.sub.3 i-Bu ##STR279## ##STR280## 1090 S 4-OCH.sub.3 i-Bu ##STR281## ##STR282## 1091 S 4-OCH.sub.3 i-Bu ##STR283## ##STR284## 1092 S 4-OCH.sub.3 i-Bu ##STR285## ##STR286## 1093 S 4-OCH.sub.3 i-Bu ##STR287## ##STR288## 1094 S 4-OCH.sub.3 i-Bu ##STR289## ##STR290## 1095 S 4-OCH.sub.3 i-Bu ##STR291## ##STR292## 1096 S 4-OCH.sub.3 i-Bu ##STR293## ##STR294## 1097 S 4-OCH.sub.3 i-Bu ##STR295## ##STR296## 1098 S 4-OCH.sub.3 i-Bu ##STR297## ##STR298## 1099 S 4-OCH.sub.3 i-Bu ##STR299## ##STR300## 1100 S 4-OCH.sub.3 i-Bu ##STR301## ##STR302## 1101 S 4-OCH.sub.3 i-Bu ##STR303## ##STR304## 1102 S 4-OCH.sub.3 i-Bu ##STR305## ##STR306## 1103 S 4-OCH.sub.3 i-Bu ##STR307## ##STR308## 1104 S 4-OCH.sub.3 i-Bu ##STR309## ##STR310## 1105 S 4-OCH.sub.3 i-Bu ##STR311## ##STR312## 1106 S 4-OCH.sub.3 i-Bu ##STR313## ##STR314## 1107 S 4-OCH.sub.3 i-Bu ##STR315## ##STR316## 1108 S 4-OCH.sub.3 i-Bu ##STR317## ##STR318## 1109 S 4-OCH.sub.3 i-Bu ##STR319## ##STR320## 1110 S 4-OCH.sub.3 i-Bu ##STR321## ##STR322## 1111 S 4-OCH.sub.3 i-Bu ##STR323## ##STR324## 1112 S 4-OCH.sub.3 i-Bu ##STR325## ##STR326## 1113 S 4-OCH.sub.3 i-Bu ##STR327## ##STR328## 1114 S 4-OCH.sub.3 i-Bu ##STR329## ##STR330## 1115 S 4-OCH.sub.3 i-Bu ##STR331## ##STR332## 1116 S 4-OCH.sub.3 i-Bu ##STR333## ##STR334## 1117 S 4-OCH.sub.3 i-Bu ##STR335## ##STR336## 1118 S 4-OCH.sub.3 i-Bu ##STR337## ##STR338## 1119 S 4-OCH.sub.3 i-Bu ##STR339## ##STR340## 1120 S 4-OCH.sub.3 i-Bu ##STR341## ##STR342## 1121 S 4-OCH.sub.3 i-Bu ##STR343## ##STR344## 1122 S 4-OCH.sub.3 i-Bu ##STR345## ##STR346## 1123 S 4-OCH.sub.3 i-Bu ##STR347## ##STR348## 1124 S 4-OCH.sub.3 i-Bu ##STR349## ##STR350## __________________________________________________________________________
TABLE 7 __________________________________________________________________________ ##STR351## COMPOUND Z G X X' D' R.sup.7 __________________________________________________________________________ XLVIII ##STR352## H.sub.2 H OH i-Bu 4-OCH.sub.3 LXXIV ##STR353## H.sub.2 OH H i-Bu 4-OCH.sub.3 LXXV ##STR354## H.sub.2 OH H i-Bu 4-OCH.sub.3 LXXVI ##STR355## H.sub.2 OH H i-Bu 4-OCH.sub.3 __________________________________________________________________________
TABLE 8 ______________________________________ ##STR356## COM- POUND OH Z X D' R.sup.7 ______________________________________ LI S i-Bu--NH ##STR357## i-Bu 4-OCH.sub.3 LII S ##STR358## ##STR359## i-Bu 4-OCH.sub.3 LIII S ##STR360## ##STR361## i-Bu 4-OCH.sub.3 ______________________________________
TABLE 9 ______________________________________ (LVII') ##STR372## COM- POUND Z G D' ______________________________________ X' ##STR373## H.sub.2 i-Bu XI' ##STR374## H.sub.2 i-Bu XII' ##STR375## H.sub.2 i-Bu XIII' ##STR376## H.sub.2 i-Bu XIV' ##STR377## H.sub.2 i-Bu XV' ##STR378## H.sub.2 i-Bu XVI' ##STR379## H.sub.2 i-Bu XVII' ##STR380## H.sub.2 i-Bu XVIII' ##STR381## O i-Bu XIX' ##STR382## H.sub.2 i-Bu XX' ##STR383## H.sub.2 i-Bu XXI' ##STR384## H.sub.2 ##STR385## LXV' ##STR386## H.sub.2 ##STR387## XXII' ##STR388## H.sub.2 ##STR389## XXIII' ##STR390## H.sub.2 ##STR391## LXVI' ##STR392## H.sub.2 ##STR393## XXIV' ##STR394## H.sub.2 ##STR395## XXV' ##STR396## H.sub.2 ##STR397## XXVI' ##STR398## H.sub.2 ##STR399## XXVII' ##STR400## H.sub.2 ##STR401## XXVIII' ##STR402## H.sub.2 i-Bu XXIX' ##STR403## H.sub.2 i-Bu XXX' ##STR404## H.sub.2 i-Bu XXXI' ##STR405## H.sub.2 i-Bu XXXII' ##STR406## H.sub.2 i-Bu ______________________________________
TABLE 10 ______________________________________ (LVIII') ##STR407## COMPOUND Z Y ______________________________________ XXXII' ##STR408## ##STR409## LXVII' ##STR410## ##STR411## ______________________________________
TABLE 11 ______________________________________ (LIX') ##STR412## COMPOUND Z X Y ______________________________________ XXXIV' ##STR413## ##STR414## H LXVIII' ##STR415## ##STR416## H XXXV' ##STR417## H ##STR418## LXIX" ##STR419## H ##STR420## La' ##STR421## H i-Bu Lb' ##STR422## H ##STR423## Lc' ##STR424## i-Bu H ______________________________________
TABLE 12 ______________________________________ (LX') ##STR425## COMPOUND Z D' ______________________________________ XXXVI' ##STR426## ##STR427## XXXVII' ##STR428## ##STR429## XXXVIII' ##STR430## i-Bu XXXIX' ##STR431## ##STR432## LVI' ##STR433## i-Bu ______________________________________
TABLE 13 ______________________________________ (LXI') ##STR434## COMPOUND Z D D' ______________________________________ XL' ##STR435## ##STR436## ##STR437## LXX' ##STR438## ##STR439## ##STR440## LXXI' ##STR441## ##STR442## ##STR443## LIV' ##STR444## ##STR445## i-Bu LXXII' ##STR446## ##STR447## i-Bu LXXIII' ##STR448## ##STR449## i-Bu ______________________________________
TABLE 14 __________________________________________________________________________ (LXII') ##STR450## COMPOUND Z G X X' D' __________________________________________________________________________ XLI' ##STR451## H.sub.2 OH H i-Bu XLII' ##STR452## O OH H i-Bu LXXXV' ##STR453## H.sub.2 OH H i-Bu XLIII' ##STR454## H.sub.2 OH H i-Bu XLIVa' ##STR455## H.sub.2 OH H i-Bu XLIVb' ##STR456## H.sub.2 OH H i-Bu XLV' ##STR457## H.sub.2 OH H i-Bu XLV□I' ##STR458## H.sub.2 OH H i-Bu XLV□II' ##STR459## H.sub.2 OH H i-Bu LXXXIII' ##STR460## O OH H i-Bu XLIX' ##STR461## H.sub.2 OH H ##STR462## LVa' ##STR463## H.sub.2 OH H i-Bu LVb' ##STR464## H.sub.2 OH H i-Bu __________________________________________________________________________
TABLE 15 __________________________________________________________________________ (LXIII') ##STR465## COMPOUND Z G X X' D' __________________________________________________________________________ XLVIII' ##STR466## H.sub.2 OH H i-Bu LXXIV' ##STR467## H.sub.2 OH H i-Bu LXXV' ##STR468## H.sub.2 OH H i-Bu LXXVI' ##STR469## H.sub.2 OH H i-Bu LXXVII' ##STR470## H.sub.2 OH H i-Bu __________________________________________________________________________
TABLE 16 ______________________________________ (LXIV') ##STR471## COMPOUND Z X D' ______________________________________ LI' i-Bu--NH ##STR472## i-Bu LII' ##STR473## ##STR474## i-Bu LIII' ##STR475## ##STR476## i-Bu ______________________________________
TABLE 17 ______________________________________ ##STR477## La' ##STR478## Le' ##STR479## Lf' ##STR480## LXXXI' ##STR481## LXXXII' ##STR482## ##STR483## LXXXV' ______________________________________
______________________________________ Mobile phase: A = 0.1% CF.sub.3 CO.sub.2 H in H.sub.2 O B = 0.1% CF.sub.3 CO.sub.2 H in CH.sub.3 CN Gradient: T = 0 min., A (95%), B (5%) T = 20 min., A (0%), B (100%) T = 22.5 min., A (0%), B (100%) ______________________________________
______________________________________ Compound K.sub.i (nM) ______________________________________ XLII 2,400 XLIVa 400 XLVIII 3,300 XLV 160 LVa 167 LI 5,000 LII 11 LXXVI 2,700 1000 100 1001 30 1002 16,000 1003 1,200 1004 1,300 1005 15 1006 470 1007 35 1008 260 1009 120 1010 125 1011 110 1012 200 1013 50 1014 130 1015 17 1016 75 1017 110 1018 65 1019 20 1020 170 1021 70 1022 170 1023 52 1024 66 1025 270 1026 20 1027 7 1028 800 1029 3,500 1031 1,400 1033 1,600 1034 1,100 1035 3,600 1036 8,000 1037 >10,000 1038 >10,000 1039 >3,000 1040 >10,000 1041 270 1044 220 1045 14 1046 1,200 1047 1,600 1048 3,300 ______________________________________
Claims (23)
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US08/424,372 US6127372A (en) | 1994-03-07 | 1995-02-24 | Sulfonamide inhibitors of aspartyl protease |
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US20758094A | 1994-03-07 | 1994-03-07 | |
US08/424,372 US6127372A (en) | 1994-03-07 | 1995-02-24 | Sulfonamide inhibitors of aspartyl protease |
PCT/US1995/002420 WO1995024385A1 (en) | 1994-03-07 | 1995-02-24 | Sulphonamide derivatives as aspartyl protease inhibitors |
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US20758094A Continuation-In-Part | 1994-03-07 | 1994-03-07 |
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US08/424,372 Expired - Lifetime US6127372A (en) | 1994-03-07 | 1995-02-24 | Sulfonamide inhibitors of aspartyl protease |
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US (1) | US6127372A (en) |
EP (1) | EP0749421B1 (en) |
JP (1) | JPH10500938A (en) |
CN (1) | CN1146201A (en) |
AT (1) | ATE184594T1 (en) |
AU (1) | AU699483B2 (en) |
CA (1) | CA2183653A1 (en) |
DE (1) | DE69512220T2 (en) |
DK (1) | DK0749421T3 (en) |
ES (1) | ES2139195T3 (en) |
GR (1) | GR3032151T3 (en) |
HK (1) | HK1012622A1 (en) |
IL (1) | IL112841A0 (en) |
MX (1) | MX9603909A (en) |
WO (1) | WO1995024385A1 (en) |
ZA (1) | ZA951688B (en) |
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